Targeted Therapeutic Solutions (TTS, a small business) is developing a first-in-class thromboprophylactic agent (TTS01) for use in the hospital setting having a rapid onset of action to dissolve clots and prevent the formation of new clots with a reduced risk of bleeding. Two thirds of venous thromboembolism (VTE) cases and deaths are hospital-acquired and is the most common preventable cause of hospital death and disability. Despite prophylaxis with low molecular weights heparins (LMWHs) or warfarin, 15%-30% patients still develop DVT. We envision that TTS101 will be a unique drug for use (1) post-surgically in knee or hip replacement patients and (2) in patients with acute thrombosis (TIA, AMI) at high-risk of bleeding presenting to the emergency room, medical intensive care units (MICUs) and other hospital-associated settings, needing rapid protection against or reversal of thrombosis. We believe TTS 101 is a new type of thromboprophylactic drug that can be used in patients in the first hours after elective surgery for prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism (PE). Our technology is based on a novel zymogen fusion protein scFv/uPA-T (consisting of lmw-scuPA-T and anti- glycophorin A (GPA)). Data to date demonstrate this construct has suitable pharmacological characteristics for our intended therapeutic use in thromboprophylaxis. Two additional features of our novel molecule that remain to be established in detail are its (1) therapeutic window and (2) safety (bleeding complications). We are proposing to work with murine models of thrombosis and bleeding that are often used to address these questions and these models are in place at our collaborator's laboratory. The mouse version of our potential scFv/uPA-T product (TTS101m) and its non-targeted analog are produced in our laboratory where we also have well established mouse models of thrombosis and bleeding. Our proposal focuses on establishing: (1) the minimum effective dose (MED) of TTS101m; (2) its safety (no bleeding predisposition) at MED in a post- operative model; (3) the duration of antithrombotic effect at 1/2 max dose. Successful completion of the AIMS provides the justification for the development of the human form of TTS101 as our lead product development candidate. The critical activities in this development program would be: (1) Creation of a humanized fusion protein capable of binding to human red blood cells; (2) Manufacture of TTS101h under good manufacturing practices (GMP); (3) IND-directed preclinical safety assessment; (4) Formation of a medical advisory board; (5) Phase 1 dose-escalation, safety and tolerability studies. Funding for further development will be pursued through grants, such as SBIR/STTR & advocacy groups (National Blood Clot Alliance, AHA), and solicitation of equity investments.